The long-term objective of this project is to systematically investigate the regulation of choroidal blood flow and the role of the choroid in ocular pressure homeostasis. Ischemic damage is thought to be the underlying cause of blindness in ocular diseases such as diabetic retinopathy and glaucoma. Because the choroid is the primary source of oxygen and nutrients for the retina, knowledge of choroidal blood flow regulation is essential for understanding, preventing and treating the vascular consequences of these and other diseases. In contrast to the previous view of the choroid as a passive vascular bed devoid of autoregulatory ability, studies during the past funding period show that choroidal blood flow is well autoregulated, particularly when arterial pressure is the manipulated variable. Moreover, the results indicate that the mechanism responsible for choroidal autoregulation is myogenic rather than metabolic (as in the retina), and that it acts to control choroidal blood volume and so minimize the fluctuations in intraocular pressure that would otherwise occur during normal variations in arterial blood pressure. The present project will continue to examine the regulation of choroidal blood flow by testing the following hypotheses: 1) a myogenic mechanism regulates the flow and volume of blood in the choroid, 2) the myogenic mechanism is modulated by neurohumoral factors, and 3) the myogenic mechanism plays a significant role in intraocular pressure homeostasis. A mathematical model based on these hypotheses serves as the conceptual framework for the project and as a dynamic 'library' for the project's results. Although the model was refined significantly during the last funding period, quantitative information for many of the model's key variables and relationships must still be obtained. To achieve this goal, the project's specific aims are: 1) to quantitate the neural and humoral control of choroidal blood flow to determine the normal myogenic set-point and the physiologic variables that modulate it, and 2) to determine the role of the choroid in intraocular pressure by determining the factors that affect choroidal blood volume. The work will be conducted in anesthetized animals instrumented to control and monitor arterial and intraocular pressures while measuring choroidal blood flow by laser-Doppler flowmetry. Most of the experiments will involve the systematic manipulation of arterial and intraocular pressures before and after selective blockade or stimulation of known vascular effector systems to quantify their effects on the choroidal pressure-flow relation and intraocular pressure. The experimental results will be used to continue refining the mathematical model so that the model accurately portrays the regulation of choroidal blood flow and its role in ocular pressure homeostasis upon completion of the project.